CN1504453A - 1,5-double substituted anthraquinone derivative, synthetic method and uses thereof - Google Patents

1,5-double substituted anthraquinone derivative, synthetic method and uses thereof Download PDF

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CN1504453A
CN1504453A CNA021447004A CN02144700A CN1504453A CN 1504453 A CN1504453 A CN 1504453A CN A021447004 A CNA021447004 A CN A021447004A CN 02144700 A CN02144700 A CN 02144700A CN 1504453 A CN1504453 A CN 1504453A
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alkoxyl group
alkyl
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黄旭山
陈荣福
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Abstract

The invention discloses a 1,5 di-substituted anthraquinone derivative represented in formula I and formula II, wherein group R is alkoxy group having 1-10 carbon atoms, or selected from alkyl, alkylamine, or amidogen alkoxy, amidogen alkyl, or phenyl with substituted alkoxy, or benzyl with substituted alkoxy, or phenyl with substituted amidogen, or benzyl with substituted amidogen, the alkyl or alkoxy can be straight chain or branched chain, and the alkyl, alkoxy, phenyl, and benzyl can all be substituted be more than one halogen from fluorine, chlorine, bromine, iodine. The derivative of the invention can act as anti-allergic, anti-inflammation and antineoplastic medicament.

Description

1, the two substituted anthraquinone derivatives of 5-and synthetic method and purposes
Technical field
The present invention relates to a kind of 1, the two substituted anthraquinone derivatives of 5-and the synthetic method of this derivative and the purposes of this derivative.
Background technology
Be present in nature and be widely used in anti-inflammatory for hundreds of years, medicine among the analgesic illness, sorrel (Rheum palmatum L.), giant knotweed (Polygonum cuspidatum Sieb.et Zucc.), Semen Cassiae (Cassia obtusifolia L.), confirm wherein quinones composition Schuttgelb (emodin) through experiment in vitro, the human scale lung carcinoma cell (human lung squamous carcinomacell) of inhibition is arranged, suppress human uterus's neck tumour (cervical carcinoma) cell strain, transferability epidermis (transformer epithelial) cell strain, the activity of leukemia (erythroleukemia) cell strain growth.
And appropriate letter (doxorubicin) microbiotic more than being separated by microorganism in early days finds that thereafter this kind compound has the inhibition activity of tumor cells; This type of Fourth Ring glucosides microbiotic (glycoside) (anthracycline glycoside antibiotic) compounds, because its structure is that bank draws letter (anthracycline) and contains Fourth Ring glucosides microbiotic (glycoside), the bank that structural body contains quinone (quinones) and fragrance three rings draws Sheng (anthracene), draws letter (anthracycline) antitumor compounds so be classified as bank.
Hydrogen-oxygen anthraquinone (hydroxyanthraquinone) constituents from Chinese medicine, rhabarberone or Schuttgelb, and the so-called bank close with anthraquinone (anthraquinone) structure draw letter (anthracycline) antitumor compounds, finds to utilize the research and development pattern that has the work activity relationship between chemical structure and physiologically active and carry out medicine.So be considered as guiding compound (lead compound), carry out the modification of compound structure, the research and development appropriate father-in-law of novel drugs wheat (mitoxantrone) from how appropriate letter (doxorubicin).The scholar in modern times further inquires into these novel drugs and seeks to reach positive effects such as increase absorbs, promotion curative effect not only in the research and development pattern of discussion pharmaceutical activity and structural relation (SAR), or towards reducing targets such as toxicity, reduction side effect.The drug development trend of these cancer chemotherapy has become the pattern of researching and developing novel drugs in recent years.
Many scholars are for 9, and the 10-anthraquinone compounds carries out structural modification, Fisher, and people such as GR are reported in 9, connection-NH (CH on the 1st, 4 side chain of 10-anthraquinone in nineteen ninety Free Radical Res Commun the 11st volume 1-3 phase 117-125 page or leaf 2) 2NH (CH 2) 2The derivative of OH side chain is found that its texture ratio connects identical side chain on the 1st, 5 or 1,8 side chain derivative more can not form the hydroxide ion free radical, and for mankind mastopathy cell's strain (MCF-7) less DNA thigh fracture is arranged.Contrivers etc. have have researched and developed a series of anthraquinone derivatives that substituting group is arranged, and show the activity of antitumor cell at cell experiment, and obtain United States Patent (USP) the 6th, 372,785B1 number and the 6th, 369,246B2 number patent.
Tam, people such as MN report 2-(1-hydrogen-oxygen alkyl)-1 in Arch Pharm Res the 23rd volume the 4th phase 283-287 page or leaf in 2000,4-bi-methoxy-9,10 anthraquinones (2-(1-hydroxyalkyl)-1,4-dimethoxy-9, the 2nd hydrogen-oxygen alkyl 10-anthraquinones) reacts the compound that forms so-called imido grpup alkyl (iminoalkyl), can present higher inhibition lymph corpuscle leukemia cell line (L1210), adenocarcinoma of lung (lung adeno-carcinoma) cell strain (A549) activity.
Yamashita, K. wait the people to draw atmosphere (anthrarufin) can suppress rabbit, and people such as Kawai K draw atmosphere (anthrarufin) to present genotoxicity (genotoxicity) via the oxidative phosphorylation (oxidative phosphorylation) of mouse liver plastosome (livermitochondria) in Cell Biol Toxicol. the 2nd volume the 4th phase 457-467 page or leaf report bank in 1986 through preceding hyperplasia by Progesterone stimulation Uterus wall mucous membrane in TohokuJ.exp.Med. the 99th volume the 1st phase 19-23 page or leaf report bank in 1969.
Summary of the invention
The purpose of this invention is to provide a kind of 1, the two substituted anthraquinone derivatives of 5-, and the synthetic method of this derivative and the purposes of this derivative.
The present invention's derivative is suc as formula the compound shown in I, the formula II,
Figure A0214470000051
Wherein, the R base is the alkoxyl group of 1 to 10 carbon atom, or selects alkyl for use, alkyl amine group, or amido alkoxyl group, and the amido alkyl, or the phenyl of alkoxyl group replacement is arranged, or the benzyl of alkoxyl group replacement is arranged; Or the phenyl of amido replacement is arranged, or the benzyl of amido replacement; Above-mentioned alkyl or alkoxyl group all can be straight chain, perhaps side chain; And the replacement of above halogens such as fluorine, chlorine, bromine, iodine can be arranged all on this alkyl, alkoxyl group, phenyl, the benzyl.
Preparation is suc as formula I, the method of compound shown in the formula II, weigh bank and draw atmosphere or 1,5-dichloride base anthraquinone (1,5-dichloroanthraquinone) place the round bottom two-neck bottle, add anhydrous methylene chloride or tetrahydrofuran (THF) and add pyridine or sodium hydride subsequently, after evenly stirring 30 minutes under 0 ℃, slowly splash into excessive halogenation vinegar compound (acyl halorides, RCOX) or mercaptan (thiols, RSH), sodium methoxide (sodium methoxide), after continuing to be stirred to room temperature or heating, reaction solution poured into get organic layer in the water, with dichloromethane extraction, remove impurity in organic layer and the dichloromethane layer amalgamation layer with washing, through anhydrous sodium sulphate absorption moisture and filtration wherein, gained solution is removed solvent with concentrating under reduced pressure, carries out purifying with the tubing string chromatography; Add solvent recrystallize such as ethanol, tetrahydrofuran (THF) or disulfoxide, can obtain formula I compound 1, the two anilide oxygen anthraquinones (1 of 5-, 5-bisacyloxyanthraquinone), and formula II compound 1, and 5-disulfide group anthraquinone (1,5-bis-thio-anthraquinones).
In the aforesaid method, mercaptan compound or halogenation vinegar raw materials of compound can select that the R base is the alkoxyl group of 1 to 10 carbon atom on its structure for use, alkyl, alkyl amine group, or amido alkyl, or the amido alkoxyl group, or the phenyl of alkoxyl group replacement is arranged, or the benzyl of alkoxyl group replacement; Or the phenyl of amido replacement is arranged, or the benzyl of amido replacement; Above-mentioned alkyl or alkoxyl group all can be straight chain, perhaps side chain; And the replacement of above halogens such as fluorine, chlorine, bromine, iodine can be arranged all on this alkyl, alkoxyl group, phenyl, the benzyl.
The pharmaceutical compositions of a kind of antianaphylaxis, inflammation, it is to contain to possess compound shown in the dosage formula I, and pharmaceutically acceptable excipient.
The pharmaceutical compositions of a kind of antianaphylaxis, inflammation, it is to contain to possess compound shown in the dosage formula II, and pharmaceutically acceptable excipient.
A kind of antitumor pharmaceutical compositions, it is to contain to possess compound shown in the dosage formula I, and pharmaceutically acceptable excipient.
A kind of antitumor pharmaceutical compositions, it is to contain to possess compound shown in the dosage formula II, and pharmaceutically acceptable excipient.
The super oxygen dismutase of a kind of influence suppresses the pharmaceutical compositions of superoxide ion generation, and it is to contain to possess compound shown in the dosage formula I, and pharmaceutically acceptable excipient.
The super oxygen dismutase of a kind of influence suppresses the pharmaceutical compositions of superoxide ion generation, and it is to contain to possess compound shown in the dosage formula II, and pharmaceutically acceptable excipient.
Description of drawings
Fig. 1 draws atmosphere (anthrarufin) to synthesize 1 by bank, and the two anilide oxygen anthraquinones of 5-(1, process diagram 5-bis-acyloxy-anthraquinone).
Fig. 21,5-disulfide group anthraquinone (1.5-bis-thio-substituted anthraquinone)
Two anilide oxygen anthraquinone (bis-acyloxy-anthraquinone) the super oxygen dismutases of compounds affect (SOD) of Fig. 3 1.5-suppress superoxide ion (superoxide anion radical, O 2 -) generation
The super oxygen dismutase of Fig. 4 1.5-bis-thio-substituted anthraquinone compounds affect (SOD) suppresses superoxide ion (superoxide anion radical, O 2 -) generation
Embodiment
The present invention's 1, two substituted anthraquinone (Anthraquinones) derivative formula I and the formula II as follows of 5-, its R base is the alkoxyl group of 1 to 10 carbon atom, alkyl, alkyl amine group, or amido alkyl, or amido alkoxyl group, or the phenyl (phenyl) of alkoxyl group replacement is arranged, or the benzyl of alkoxyl group replacement (benzyl); Or the phenyl (phenyl) of amido replacement is arranged, or the benzyl of amido replacement (benzyl).Above-mentioned alkyl or alkoxyl group all can be straight chain, perhaps side chain; And the replacement of above halogens such as fluorine, chlorine, bromine, iodine can be arranged all on this alkyl, alkoxyl group, phenyl (phenyl), the benzyl (benayl).
1, the synthetic method of the two substituted anthraquinones of 5-
The present invention as shown in Figure 1 and Figure 2, utilization mercaptan (thiols, RSH) compound or halogenation vinegar compound (acyl halorides, RCOX) under felicity condition, draw atmosphere (anthrarufin) or 1 by bank, the two hydroxyanthraquinones (1 of 5-, 5-Dihydroxylanthraquinone) for raw material synthesizes 1, the two substituted anthraquinone derivatives of 5-; This halogenation vinegar compound (acyl halorides, RCOX) can select for use and fluoridize vinegar compound (acyl flurorides, RCOF), chlorination vinegar compound (acyl chlorides, RCOCI), bromination vinegar compound (acyl bromorides, RCOBr), iodate vinegar compound (acyliodorides, RCOI).So-called suitable condition means alkaline state, for example adds pyridine (pyridine), sodium methylate (sodium methoxide), sodium hydride (NaH).
Weigh bank and draw atmosphere (anthrarufin) or 1,5-dichloroanthraquinone places the round bottom two-neck bottle, adds anhydrous methylene chloride (CH 2Cl 2) or tetrahydrofuran (THF) (THF), add pyridine (pyridine) or sodium hydride (NaH) subsequently, after evenly stirring 30 minutes under 0 ℃, slowly splash into excessive halogenation vinegar compound (acyl halorides, RCOX) or mercaptan (thiols, RSH), sodium methoxide (sodium methoxide), continue to be stirred to reaction solution to be poured into after room temperature or the heating and get organic layer in the water, with methylene dichloride (CH 2Cl 2) extraction, with the impurity in flush away organic layer and the dichloromethane layer amalgamation layer, through anhydrous sodium sulphate absorption moisture and filtration wherein, gained solution is removed solvent with concentrating under reduced pressure, carries out purifying with the tubing string chromatography with water; With ethanol, tetrahydrofuran (THF) (THF) or disulfoxide (dimethyl sulfoxide, solvent recrystallize such as DMSO), can obtain formula I compound 1, the two anilide oxygen anthraquinones (1 of 5-, 5-bisacyloxy-anthraquinone), and formula II compound 1, and 5-disulfide group anthraquinone (1,5-bis-thio-anthraquinones).
Be applicable to and state mercaptan (thiols on the present invention, RSH) compound or halogenation vinegar compound (acyl halorides, RCOX) raw material, can select that the R base is the alkoxyl group of 1 to 10 carbon atom on its structure for use, alkyl, alkyl amine group, or amido alkyl, or amido alkoxyl group, or at the phenyl (phenyl) of alkoxyl group replacement, or the benzyl of alkoxyl group replacement (benzyl); Or the phenyl (phenyl) of amido replacement is arranged, or the benzyl of amido replacement (benzyl).Above-mentioned alkyl or alkoxyl group all can be straight chain, perhaps side chain; And the replacement of above halogens such as fluorine, chlorine, bromine, iodine can be arranged all on this alkyl, alkoxyl group, phenyl (phenyl), the benzyl (benzyl).
Method 1 as shown in Figure 1: weigh the 4.25mmol bank and draw atmosphere (anthrarufin) to add 20ml pyridine (pyridine) in 150ml anhydrous methylene chloride (CH 2Cl 2), under 0 ℃ of nitrogen, slowly splash into the halogenation vinegar compound (acyl halorides) that 10mmol is dissolved in anhydrous methylene chloride, place the round bottom two-neck bottle.After backflow 1-2 hour reaction solution is poured in the 250ml water, get organic layer with dichloromethane extraction, with water with the impurity in flush away organic layer and the dichloromethane layer amalgamation layer, through anhydrous sodium sulphate absorption moisture and filtration wherein, gained solution is removed solvent with concentrating under reduced pressure, carries out purifying with the tubing string chromatography; Recrystallize.
Method 2: weigh the 4.25mmol bank and draw atmosphere (anthrarufin) to add 20ml tetrahydrofuran (THF) (THF), sodium hydride (NaH) in 250ml anhydrous tetrahydro furan (THF), under 0 ℃ of nitrogen, slowly splash into 10mmol and be dissolved in the halogenation vinegar compound (acyl halorides) of anhydrous methylene chloride, place the round bottom two-neck bottle.After backflow 1-2 hour reaction solution is poured in the 250ml water, with methylene dichloride (CH 2Cl 2) get organic layer, with the impurity in flush away organic layer and the dichloromethane layer amalgamation layer, through anhydrous sodium sulphate absorption moisture and filtration wherein, gained solution is removed solvent with concentrating under reduced pressure, carries out purifying with the tubing string chromatography with water; Recrystallize.
The compound of the present invention's acquisition can be confirmed its structure according to the information of following equipment, and all temperature are centigradetemperature; Use molten some determinator of BUCHI530, do not proofreaied and correct behind the mensuration fusing point.Chromatography uses the tubing string (E.Merck company product, 70-230 sieve aperture) of silica gel body.The 1H-NMR (Nuclear Magnetic Resonance) spectrum is used Fan's 300MHz Gemini-300 (Varian GEMINI-300); The δ value is with hundred very much (ppms) of tetramethyl-silicon (tetramethylsilane) as internal standard; Infrared spectrum (KBr) be Parker-Ai Demen spectrometer (Perkin-Elmer 983Gspectrometer) go up record Fourier formula conversion value (Fourier-transform-IR spectra, KBr); General specified mass spectrum (Mass spectra, EI is 70eV) via smooth MAT TSQ-46 of fen and MAT TSQ-700 (Finnigan MAT TSQ-46 and Finnigan MAT TSQ-700); UV spectrum (UV spectra) is to measure with Tianjin, island UV-160 (Shimadzu UV-160).
Normal human cell finally enters aging (replicative senescence) state that duplicates that does not have division (nondividing) through limited cell fission.At the continuous interkinesis of cell, the end problem of duplicating occurs in fringes of chromosome (telomere) and shortens with finally old and feeble.Harley, people such as CB. be in nineteen ninety Nature the 345th volume 458-460 page or leaf report, cell fission after stain colour solid telomere (telomere) each time duplicate the loss limited degree, present and cross over " circadian clock body clock " as normal somatic cell and increase life degree.Thereby anti-proliferative effect (antiproliferative) mechanism for some cancer therapy drugs has many hypothesis.People such as Taatjes D were in the 40th the 8th phase of volume of J Med Chem in 1997,1276-1278 page or leaf report commodity Ya Dixing (adriamycin by name, doxorubicin) be considered to important clinically cancer therapy drug, because this type of bank draws letter (anthracycline) antitumor compounds to be used in leukemia (leukemias), lymphoma (lymphomas), sarcoma (sarcomas) and cancer malignant tumours (malignancy) such as (carcinomas) widely.
It is that proliferation function two aspects at inflammation and state propose suitable effective treatment because fringes of chromosome enzyme (telomerase) is a potential high selectivity target that many evidence how appropriate letters of explanation (doxorubicin) produce antitumous effect.Mordente, people such as A are in calendar year 2001 IUBMB Life the 52nd volume 1-2 phase 83-88 page or leaf report, it may be to cause apoptosis (apoptosis) owing to produce free radical (free radicals) that bank draws letter (anthracycline) antitumor compounds to produce drug effect, bank draws letter to combine with DNA or intercalation of DNA structure, active cells information bang path, the activity of inhibition heterodoxy enzyme (topoisomerase II).Free radical (free radicals) and reactive oxygen species (active oxygen species) draw at therapeutic activity and bank and serve as key role aspect the side effect of containing ketone (anthraenone) derivative.The product of the lipid peroxidation that in chronically inflamed tissue, is caused, all can cause the dna damage of this tissue as peroxy radical (peroxyradicals), cell toxicant aldehyde (cytotoxic aldehydes) and alkoxy free group oxygenants such as (alkoxy radical), and improve the danger that cancer takes place.
The active oxygen content that belongs to enzyme (ROS) is enough to jeopardize health in vivo, increases acute infection and inflammation.Active oxygen belongs to the oxidative damage that enzyme (ROS) causes, and is linked with photoaging (photoaging), radiation murder by poisoning (radiation toxicity), cataract (cataract) or maculopathy (maculardegeneration); More relevant with local asphyxia (ischemia), and cause some immunity (immune) cell function to reduce.Polyphenoils (Antioxidants) is that some are enough to protect life entity, reduces the material of oxidative damage crisis or antagonism oxidative damage, and can present the prevention or alleviation (progression) effect of distinct program for disease.(the polymorphonuclear neutrophilic leukocytes of forming core white cell more than the known host, PMN) be the main protective immunity system of a kind of antagonism extracellular bacterium (host-protective immune system), the polymorphic nucleus white cell is called neutrophils (Neutrophils) again, neutrophils presents at the endotheliocyte (endothelial cells) of blood vessel is stained with sticking (adhesion) phenomenon, be a kind of iuntercellular regulatory factor (inflammatory mediators) back of being stained with viscoelastic element (ICAM-1) and being exposed to inflammation at endothelial cell surface through promoting regulation and control (up-regulated).
The compound of the present invention's acquisition is through the strain of rat neuroglial cytoma (rat glioma C6 cells), the tetrazolium sodium of hepatoma cell strain (human hepatoma G2 cells) is analyzed (XTT, sodium 3,3 '-1-[(phenylamino) and carbonyl]-3,4-terazolium}-bis (4-methoxy-6-nitor) benzene sulfonic acid hydrate assay), suppress the growth of tumour cell test, and the lipid peroxidation activity test.As shown in Table 1, (α-tocopherol) raw material (starting material) compares for the compound of the present invention's acquisition and the appropriate father-in-law of control group wheat (mitoxantrone), vitamin C (ascorbicacid), vitamin D.The IC of the appropriate father-in-law of wheat (mitoxantrone) poisoning Hep G2 JEG-3 50Be worth 2.0 μ M, and compound 1b, the 1f of the present invention's acquisition, 1n to suppress tumor cell growth activity be its 5 to 100 times, kill the IC of Hep G2 JEG-3 50It is 0.02,0.04,0.4 μ M in addition that value is divided.The lipid peroxidation specific activity control group of The compounds of this invention is low.This pair fourth anilide oxygen derivative (bisbutyryloxy analogue 1b) has the poisoning Hep G2 JEG-3 activity of brute force, than the appropriate father-in-law of control group wheat up to 100 times, and two chloro benzene anilide oxygen derivatives (bischlorobenzoyl analogue 1f) than control group up to 50 times.Tumor cell growth activity is lower the 1st, 5 of anthraquinone (anthraquinone) structure the derivative (phenylpropionyloxy analogue 1n) of the bis-phenol base third anilide oxygen base, and the lipid peroxidation activity increases, and is more than control group.With respect to vitamin E or vitamin C, compound 1c, 1d, 1e, 1k there is no in the experiment of Wistar rat brain tissue and increase lipid peroxidation activity (lipidperoxidation), but present preceding oxidation activity (prooxidation).Show that by this experimental data the compound of The compounds of this invention acquisition is not good polyphenoils (antioxidant) except that 1n, but have the activity that prevents lipid peroxidation.Through the more relevant 1n antagonism vitamin Es or the lipid peroxidation activity research of vitamin C, as shown in Table 2, the 1n of 0.01mM concentration has 50% lipid peroxidation activity; Vitamin C is active to reduce 10%; Vitamin E is at 0.1mM concentration and non-activity.Demonstration 1n is than vitamin E or vitamin C has better anti-oxidant activity; Therefore 1n can protect normal cell to avoid being subjected to oxidative damage.Confirm that from above-mentioned physiologically active data the existing inhibition tumor cell growth activity of compound 1n also has the anti peroxidation of lipid activity.
And the IC of the present invention's compound 2a, 2h poisoning rat neuroglial cytoma strain C6 50Value is respectively 0.02 and 0.05 μ M, and is more remarkable than the appropriate father-in-law of control group wheat (mitoxantrone) 0.07 μ M.And compound 2i draws atmosphere (anthrarufin) to have better lipid peroxidation activity (lipid peroxidation) than vitamin E, vitamin C, the appropriate father-in-law of wheat, raw material bank.Gutteridge, people such as J. are subjected to Fe in Free Radic.Res.Commun. in 1993 the 19th volume the 141st page of report level of lipid peroxidation and lipid 2+The mda that produces after the oxidation (malondialdehyde) is relevant with bathyran (2-thiobarbituric acid) effect colour generation.The anthraquinone of the present invention's acquisition (anthraquinone) compound causes possessing preceding oxidation activity (prooxidation) owing to generate hydroxyl free radical.Had many data declaration compounds to have its lytic activity of lipid peroxidation, but protective tissue avoid being subjected to the injury of free radical.The appropriate father-in-law of lipid peroxidation specific activity wheat (mitoxantrone) as compound 2a, 2d, 2e, 2j, 2k is better, and wherein to suppress tumor cell growth activity also good than the appropriate father-in-law of wheat for 2d, 2e, 2j, 2k.The appropriate father-in-law of two ethyl sulfenyl derivatives (bisethylthioanalogue 2a), biconjugate-amido phenolic group sulfenyl derivative (bis (p-amino-phenylthio 2h)) poisoning rat neuroglial cytoma strain C6 specific activity wheat is good.Though compound 2i draws atmosphere (anthrarufin) to have better lipid peroxidation activity (lipid peroxidation) than vitamin C, vitamin E, the appropriate father-in-law of wheat, raw material bank; But as shown in Table 2, compound 2a, 2d, 2e, 2i, 2j, 2k there is no good lipid peroxidation activity.As shown in Table 3, the lipid peroxidation of vitamin C is active to reduce 10%, and vitamin E is at 0.1mM concentration and non-activity, and 0.01mM compound 2i lipid peroxidation activity is 24%.
And the present invention's compound carries out the Neutrophils super oxygen dismutase of influence (SOD) inhibition superoxide ion (supcroxide anion radical, O 2 -) generation after 1 hour, find 1, with 6 compounds such as 1d, 1h, 1i, 1k, 1l, 1n as shown in Figure 3, have the super oxygen dismutase of preferable influence (SOD) and suppress superoxide ion (supcroxide anion radical, O in the 5-bis-acyloxy-anthraquinone compound 2 -) the generation effect.1, with 6 compounds such as 2c, 2d, 2f, 2g, 2h, 2k as shown in Figure 4, have the super oxygen dismutase of preferable influence (SOD) and suppress superoxide ion (superoxide anionradical, O in the 5-bis-thio-substitutedanthraquinone compound 2 -) the generation effect.
As mentioned above, pharmaceutical compositions of the present invention can use various preparations performance curative effects, can remove in essence and draws Sheng (anthracene) bad inflammation and hormesis that compound brought out with bank.Therefore, effective in cure pharmaceutical compositions should comprise a kind of The compounds of this invention of significant quantity at least, with pharmaceutically acceptable vehicle.Compound of the present invention has the effect that suppresses proliferative effect (hyperproliferative) and treatment tumour.
The present invention's compound is according to adding various vehicle, carrier in case of necessity, or the additive salt of tolerable acid in thinner and the pharmacy forms the constituent with drug effect.That these preparations can be is for oral administration, rectum is thrown solid dosage, liquid dosage form with it, or the injection type of parenteral use, or directly applies the ointment dosage form in affected part.These solid dosages are to collapse class tackiness agents such as powder, ethanol, glycerine according to known formulation method in adding starch, carboxylic acid methyl sodium cellulosate and so on, or Magnesium Stearate, lactose and make lozenge or filling in capsule or make suppository and so on solid preparation.Use the aqueous solution, the salts solution of The compounds of this invention to make its pH-value pH value reach suitable degree, and make injection or other liquors in interpolation auxiliary agent, emulsifying agent with phosphoric acid salt damping fluid adjustment potential of hydrogen.The mixed various bases of the additive salt of tolerable acid also can be made into ointment dosage form according to known formulation method in The compounds of this invention or the pharmacy.Compound with the present invention is that the prepared pharmaceutical compositions of principal constituent can apply to the drug effect that mammal produces branch, and the dosage of generally offeing medicine can need allotment with symptom, is generally everyone each 50～300mg, every day 3 times.
Activity experiment
Be to carry out relevant antioxidant action of the present invention, the condition of experiments such as antitumor action below.Each experiment comprises proliferative effect (hyperproliferative) and/or Green Tea Extract, the active oxygen effect of suppressing.
Suppress to grow up and analyze
Suppress the tetrazolium sodium of growth of tumour cell and analyze (XTT, sodium 3,3 '-1-[(phenylamino) and carbonyl]-3,4-terazolium}-bis (4-methoxy-6-nitor) benzene sulfonic acid hydrate assay), through the strain of rat neuroglial cytoma (rat glioma C6cells), hepatoma cell strain (human hepatoma G2 cells, Hep G2).With 2.5 * 10 4Cells/ml inserts 96 porose disc culture dish, cultivates in advance 24 to 72 hours with perfect medium (complete medium).Throwing and the present invention's compound 72 hours is after tetrazolium sodium (XTT) analysis obtains the concentration (IC of 50% inhibition cell strain 50, mg/ml).
Lipid peroxidation activity test (Assay of Lipid Peroxidation)
Get the cerebral tissue of fresh Wistar rat, add 0 ℃ Cray uncle damping fluid (Kreb ' sbuffer), after with the Dow homogenizer mouse brain being homogenized, changeed low-temperature centrifugations 10 minutes with per minute 2530.Get the about 500 μ l of clear liquid on the every centrifuge tube, add in the test group test tube of having numbered, do not add two groups of lipids simultaneously; The one group: oxidizer and desire are not surveyed compound in addition to add disulfoxide (DMSO); Another group adding disulfoxide and oxygenant do not add desire survey compound in addition and all organize in contrast.Add 60 μ l Crays uncles damping fluid (kreb ' s buffer) more respectively and prepare in advance and contain 30 μ l disulfoxide (DMSO) solution that desire surveys compound to the lipid of test group test tube, leave standstill and mixed solution was fully acted in 10 minutes.Add 10 μ l copperas solutions respectively and organize test tube, impelling lipid oxidation and contrast usefulness, and three groups of test tubes are placed 37 ℃ of water-baths in each.After 30 minutes, take out test tube and add that 10 μ l trichloroacetic acid solutions (TCA solution) mix so that the protein denaturation of remnants adds 200 μ l, two mercaptan barbituric acid solution (TBA solution) as photoghraphic coupler.Wherein trichloroacetic acid solution (TCA soluiton) is to be 4% (w/v) with 0.3N dissolving with hydrochloric acid Tricholroacetic Acid (trichloroacetic acid) concentration.Two mercaptan barbituric acid solution (TBAsolution) are the water preparations with 0.5g two mercaptan barbituric acids (2-thiobarbituric acid) and 50ml Glacial acetic acid adding 50ml.Measure its light absorption value with 532nm under UV, lipid peroxidation activity experiment calculation formula is as follows:
Inhibiting rate (Inhibition) (%)=(Cx-Ax)/(Cx-N) * 100%
Cx: oxygen-free agent and desire are surveyed the light absorption value of the disulfoxide solution of compound.
N: only contain oxygenant and do not contain the light absorption value that desire is surveyed the disulfoxide solution of compound
Ax: contain the light absorption value that oxygenant and desire are surveyed the disulfoxide solution of compound
Neutrophils (neutrophil; PMN) preparation
Gather venous blood from adult healthy volunteers, (20unit/ml) works as anti-coagulant with heparin.Ficoll (Ficoll) gradient centrifugation is adopted in the separation of Neutrophils, centrifugal back with hypotonic solution the removal (Boyum, 1974) of rising brokenly of residual red blood corpuscle.Be summarized as follows: in the blood and 3% glucosan (dextran) of 50ml centrifuge tube mixing equal-volume, leave standstill in the room temperature treated most of erythrosedimentation in 20-30 minute after, the blood plasma of white cell is rich on careful collection upper strata, at 4 ℃, centrifugal 15 minutes of 250 * g, the collecting cell throw out is broken up, and suspends again with 8ml phosphoric acid buffer normal saline solution (PBS, phosphate buffered saline).This cell suspending liquid injected gently poly-multitudinous sugar (Ficoll) solution (Histopaque1077, Sigma) upper strata that 6ml, density are 1.077g/ml is housed in advance.In 20 ℃, 400 * g continuously centrifuged 40 minutes is removed the upper strata all liquid again, and left cell precipitation thing is a neutrophils, mixes a little red blood corpuscle.Breaing up the cell precipitation thing was suspended 30 seconds with 0.2% sodium-chlor (NaCl) of 6ml, 1.8% sodium-chlor that adds rapidly 6ml is opened solution answer etc., again in 20 ℃, centrifugal 3 minutes of 120 * g, gained cell precipitation thing cleans once with phosphoric acid buffer normal saline solution (PBS), get ten thousand cells of 1-2 at last and beat sheet through golden Sha's soil (Giemsa) solution-dyed with the centrifugal pelleter of cell specimen (cytospin), examine under a microscope the cell kenel, do the cell purity test, almost completely be the multinuclear Neutrophils, purity is generally greater than 95%.Neutrophils through preparing is suspended in the writing brush gram buffered salt solution (HBSS) standby at last.
The i experimental data is with mean value ± mean value standard error (mean ± S.E.M.) expression of measurement.Come the statistical significance of check data respectively with list or double factor analysis of variance (AVOVA) according to the experiment needs.When analysis of variance is meaningful, relatively and the variant difference that has been considered as statistical significance with P＜0.05 whether of the mean value between the control group with road mud (Dunnett ' s test).Concentration-response effect (concentration-dependency) relation is to do this for examining and determine (Student ' s st-test) with the linear regression slope of concentration-reaction to zero, has been considered as the difference of statistical significance with P＜0.05.The super oxygen dismutase of compounds affect (SOD) suppresses superoxide ion (superoxide anionradical, O 2 -) generation make chart after 1 hour.
Embodiment
The following example is described the present invention's preparation method.
Embodiment 1
1, the two anilide oxygen anthraquinones (1,5-bisacyloxyanthraquinone, 1) of 5-
Method 1: weigh the 4.25mmol bank and draw atmosphere (anthrarufin) to add 20ml pyridine (pyridine) in 150ml anhydrous methylene chloride (CH 2Cl 2), under 0 ℃ of nitrogen, slowly splash into the halogenation vinegar compound (acyl halorides) that 10mmol is dissolved in anhydrous methylene chloride, place the round bottom two-neck bottle.After backflow 1-2 hour reaction solution is poured in the 250ml water, get organic layer with dichloromethane extraction, with water with the impurity in flush away organic layer and the dichloromethane layer amalgamation layer, through anhydrous sodium sulphate absorption moisture and filtration wherein, gained solution is removed solvent with concentrating under reduced pressure, carries out purifying with the tubing string chromatography; Recrystallize.
Method 2: weigh the 4.25mmol bank and draw atmosphere (anthrarufin) to add 20ml tetrahydrofuran (THF) (THF), sodium hydride (NaH) in the 250ml anhydrous tetrahydro furan, under 0 ℃ of nitrogen, slowly splash into 10mmol and be dissolved in the halogenation vinegar compound (acyl halorides) of anhydrous methylene chloride, place the round bottom two-neck bottle.After backflow 1-2 hour reaction solution is poured in the 250ml water, with methylene dichloride (CH 2Cl 2) get organic layer, with the impurity in flush away organic layer and the dichloromethane layer amalgamation layer, through anhydrous sodium sulphate absorption moisture and filtration wherein, gained solution is removed solvent with concentrating under reduced pressure, carries out purifying with the tubing string chromatography with water; Recrystallize.
1, and two (the third anilide the oxygen)-anthraquinones of 5-(1,5-Bis (propionyloxy)-anthraquinone, la)
Make this compound according to method 1, be recrystallised to yellow needle crystal, productive rate 55% through ethanol;
m.p.230-231℃； 1H-NMR(CDCl 3)δ：1.34(t，J＝7.5Hz，6H)，2.80(q，J＝7.5Hz，4H)，7.37(d，J＝8.1Hz，2H)，7.75(t，J＝8.0Hz，2H)，8.16(d，J＝7.7Hz，2H)；FTIR(KBr)：1759，1674cm -1；UVλ max(CHCl 3)nm(log)：318(2.48)；MSm/z＝352(4，M +)，296(23)，240(100)；Anal.C 20H 16O 6(C，H).
Embodiment 2
1, and two (fourth anilide the oxygen)-anthraquinones of 5-(1,5-Bis (butyryloxy)-anthraquinone, 1b)
Make this compound according to method 1, be recrystallised to yellow needle crystal, productive rate 59% through ethanol; M.p.211-213 ℃; 1H-NMR (CDCl 3) δ: 1.1 (t, J=7.4Hz, 6H), 1.83-1.90 (m, 4H), 2.75 (t, J=7.5Hz, 4H), 7.36 (d, J=8.0Hz, 2H), 7.74 (t, J=9Hz, 2H), 8.16 (d, J=7.8Hz, 2H); 13C-NMR (CDCl 3) δ: 181.14,172.03,150.08,135.93,134.88,129.65125.63,124.45,36.15,18.04,13.75; UV λ Max(CHCl 3) nm (log): 319 (2.51) FTIR (KBr) 1757,1676cm -1MS m/z 380 (3, M +), 310 (22), 240 (100); Anal.C 22H 20O 6(C, H).
Embodiment 3
1, and two (acetyl group the oxygen)-anthraquinones of 5-(1,5-Bis (hexanoyloxy)-anthraquinone, 1c)
Make this compound according to method 1, be recrystallised to yellow needle crystal, productive rate 74% through ethanol; M.p.183-184 ℃; 1H-NMR (CDCl 3) δ: 0.95 (t, J=7.1Hz, 6H), 1.38-1.49 (m, 8H), 1.84 (q, J=7.4Hz, 4H), 2.76 (t, J=7.7Hz, 4H), 7.40 (dd, J=7.8,1.0Hz, 2H), 7.74 (t, J=8.1,7.8Hz, 2H), 8.16 (t-like, J=7.7,2.3Hz, 2H); 13C-NMR (CDCl 3) δ: 181.14,172.22,150.10,135.93,134.87,129.64,125.63,124.45,34.26,31.35,24.18,22.39,13.97; UV λ Max(CHCl 3) nm (log) 318 (2.44); FTIR (KBr) 1755,1676cm -1MS m/z 436 (4, M +), 338 (24), 240 (100); Anal.C 26H 28O 6(C, H).
Embodiment 4
1, and two (2-trimethylammonium acetyl group the oxygen)-anthraquinones of 5-(1,5-Bis (pivaloyloxy)-anthraquinone, 1d)
Make this compound according to method 2, be recrystallised to yellow needle crystal, productive rate 25% through ethanol; M.p.166-167 ℃; 1H-NMR (CDCl 3) δ: 1.47 (s, 18H), 7.31 (d, J=8.1Hz, 2H), 7.72 (d, J=8.0Hz, 2H), 8.16 (d, J=7.5Hz, 2H), 13C-HMR (CDCl 3) δ: 181.00,176.66,150.40,135.98,134.62,129.38,125.59,124.78,39.21,27.23; UV λ Max(EtOH) nm (log) 363 (1.40); FTIR (KBr) 1751,1670cm -1MS m/z 408 (3, M +), 324 (23), 240 (100); Anal.C 24H 24O 6(C, H).
Embodiment 5
1, and two (benzyl anilide the oxygen)-anthraquinones of 5-(1,5-Bis (benzoyloxy)-anthraquinone, 1e)
Make this compound according to method 1, be recrystallised to yellow needle crystal, productive rate 76% through ethanol; M.p.336-338 ℃ of (lit. [13]Mp342 ℃); 1H-NMR (CDCl 3) δ: 7.50 (d, J=7.9Hz, 2H), 7.56 (t, J=7.7Hz, 4H), 7.68 (t, J=7.3Hz, 2H), 7.77 (t, J=7.9Hz, 2H), 8.17 (d, J=7.7Hz, 2H), 8.29 (d, J=7.7Hz, 4H); UV λ Max(CHCl 3) nm (log) 340 (0.69); FTIR (KBr) 1734,1672cm -1MS m/z 448 (4, M +), 105 (100); Anal.C 28H 16O 6(C, H).
Embodiment 6
1, and two (2-chloro benzene anilide the oxygen)-anthraquinones of 5-(1,5-Bis (2-chlorobenzoyl) anthraquinone, 1f)
Make this compound according to method 2, (THF) is recrystallised to yellow needle crystal through tetrahydrofuran (THF), productive rate 39%; M.p.254-255 ℃; 1H-NMR (CDCl 3) δ: 7.47-7.55 (m, 8H), 7.80 (t, J=7.9Hz, 2H), 8.22 (d, J=7.8Hz, 2H), 8.39 (d, J=7.7Hz, 2H); UV λ Max(CHCl 3) nm (log ε) 334 (2.20); FTIR (KBr) 1747,1672cm -1MS m/z 516 (2, M +), 139 (100); Anal.C 28H 14Cl 2O 6(C, H).
Embodiment 7
1, and two (3-chloro benzene anilide the oxygen)-anthraquinones of 5-(1,5-Bis (3-chlorobenzoyl)-anthraquinone, 1g)
Make this compound according to method 2, (THF) is recrystallised to yellow needle crystal through tetrahydrofuran (THF), productive rate 49%; M.p.301-302 ℃; 1H-NMR (CDCl 3) δ: 7.50-7.52 (m, 4H), 7.65 (d, J=7.4Hz, 2H), 7.79 (t, J=7.9Hz, 2H), 8.16-8.19 (m, 4H), 8.26 (s, 2H); UV λ Max(CHCl 3) nm (log) 351 (0.33); FTIR (KBr) 1744,1674cm -1MS m/z516 (5, M +), 141 (35), 139 (100); Anal.C 28H 14Cl 2O 6(C, H).
Embodiment 8
1, and two (4-chloro benzene anilide the oxygen)-anthraquinones of 5-(1,5-Bis (4-chlorobenzoyl)-anthraquinone, 1h)
Make this compound according to method 2, (THF) is recrystallised to yellow needle crystal through tetrahydrofuran (THF), productive rate 69%; M.p.327-328 ℃; 1H-NMR (CDCl 3) δ: 7.50 (d, J=7.9Hz, 2H), 7.54 (d, J=8.4Hz, 4H), 7.78 (t, J=7.9Hz, 2H), 8.16 (d, J=7.9Hz, 2H), 8.22 (d, J=8.4Hz, 4H); UV λ Max(CHCl 3) nm (log) 351 (1.77); FTIR (KBr) 1736,1676cm -1MS m/z 516 (2, M +), 139 (100); Anal.C 28H 14Cl 2O 6(C, H).
Embodiment 9
1, two (2,4-dichloride base benzene anilide the oxygen)-anthraquinones of 5-(1, and 5-Bis (2,4-dichlorobenzoyl)-anthraquinone, 1i)
Make this compound according to method 2, (THF) is recrystallised to yellow needle crystal through tetrahydrofuran (THF), productive rate 38%; M.p.310-312 ℃; FTIR (KBr) 1740,1668cm -1MS m/z586 (4, M +), 421 (25), 240 (56), 173 (100); HRMS m/z:Calcd.for C 28H 12Cl 4O 6: 514.1464.Found:514.1478.
Embodiment 10
1, and two (2-methylbenzene anilide the oxygen)-anthraquinones of 5-(1,5-Bis (2-toluoyloxy)-anthraquinone, 1j)
Make this compound according to method 1, (THF) is recrystallised to yellow needle crystal through tetrahydrofuran (THF), productive rate 68%; M.p.262-263 ℃; 1H-NMR (CDCl 3) δ: 2.68 (s, 6H), 7.35 (d, J=7.6Hz, 2H), 7.39 (t, J=7.6Hz, 2H), 7.49-7.53 (m, 4H), 7.78 (t, J=7.9Hz, 2H), 8.19 (dd, J=8.1,0.1Hz, 2H), 8.35 (t, J=7.7,0.7Hz, 2H); 13C-NMR (CDCl 3) δ: 181.15,165.55,150.21,141.57,136.01,134.93,132.86,131.91,131,69,129.89,128.39,126.03,125.84,124.71,21.76; UV λ Max(CHCl 3) nm (log) 314 (1.56); FTIR (KBr) 1736,1674cm -1MS m/z 476 (2, M +), 119 (100); Anal.C 30H 20O 6(C, H).
Embodiment 11
1, and two (3-methylbenzene anilide the oxygen)-anthraquinones of 5-(1,5-Bis (3-toluoyloxy)-anthraquinone, 1k)
Make this compound according to method 2, (THF) is recrystallised to yellow needle crystal through tetrahydrofuran (THF), productive rate 28%; M.p.269-270 ℃; 1H-NMR (CDCl 3) δ: 2.47 (s, 6H), 7.44 (t, J=7.6Hz, 2H), 7.48-7.50 (m, 4H), 7.76 (t, J=8.0Hz, 2H), 8.09 (d, J=6.7Hz, 4H), 8.17 (d, J=7.7Hz, 2H); 13C-NMR (CDCl 3) δ: 181.05,165.28,150.25,138.52,135.94,134.91,134.56,130.96,129.78,129.34,128.60,127.67,125.94,124.60,21.36; UV λ Max(CHCl 3) nm (log) 310 (1.84); FTIR (KBr) 1732,1674cm -1MS m/z 476 (4, M +), 119 (100); Anal.C 30H 20O 6(C, H).
Embodiment 12
1, and two (4-methylbenzene anilide the oxygen)-anthraquinones of 5-(1,5-Bis (4-toluoyloxy)-anthraquinone, 1l)
Make this compound according to method 2, (THF) is recrystallised to yellow needle crystal through tetrahydrofuran (THF), productive rate 39%; M.p.331-332 ℃; 1H-NMR (CDCl 3) δ: 2.47 (s, 6H), 7.36 (d, J=8.0Hz, 4H), 7.49 (dd, J=7.8,1.0Hz, 2H), 7.75 (t, J=7.9Hz, 2H), 8.17 (d, J=7.8Hz, 4H); UV λ Max(CHCl 3) nm (log) 318 (0.90); FTIR (KBr) 1736,1672cm -1MSm/z 476 (5, M +), 119 (100); Anal.C 30H 20O 6(C, H).
Embodiment 13
1, and two (phenolic group benzene anilide the oxygen)-anthraquinones of 5-(1,5-Bis (phenylacetyloxy)-anthtaquinone, 1m)
Make this compound according to method 1, (THF) is recrystallised to yellow needle crystal through tetrahydrofuran (THF), productive rate 35%; M.p.202-203 ℃; 1H-NMR (CDCl 3) δ: 4.10 (s, 4H), 7.30 (t, J=7.4Hz, 2H), 7.33 (dd, J=8.0,0.8Hz, 2H), 7.37 (t, J=7.6Hz, 4H), 7.46 (d, J=7.4Hz, 4H), 7.74 (t, J=8.0Hz, 2H), 8.18 (t, J=7.8,0.8Hz, 2H); 13C-NMR (CDCl 3) δ: 181.06,170.12,149.99,135.87,134.95,133.33,129.76,129.57,128,63,127.31,125.83,124.28,41.13; UV λ Max(CHCl 3) nm (log) 318 (2.20); FTIR (KBr) 1736,1672cm -1MSm/z 358 (5, M +), 240 (94), 118 (100); Anal.C 30H 20O 6(C, H).
Embodiment 14
1, and 5-(the bis-phenol base third anilide oxygen)-anthraquinone (1,5-Bis (phenylpropionyloxy)-anthraquinone, 1n)
Make this compound according to method 1, (THF) is recrystallised to yellow needle crystal through tetrahydrofuran (THF), productive rate 62%; M.p.219-220 ℃; 1H-NMR (CDCl 3) δ: 3.10 (s, 4H), 3.17 (t, J=7.9,1.4Hz, 4H), 7.22-7.35 (m, 12H), 7.74 (t, J=7.9Hz, 2H), 8.16 (dd, J=7.7,0.8Hz, 2H), 13C-NMR (CDCl 3) δ: 181.08,171.35,149.97,140.39,135.88,134.96,129.62,128.57,128,47,126.36,125.75,124.33,35.86,30.58; UV λ Max(CHCl 3) nm (log) 318 (1.10); FTIR (KBr) 1761,1676cm -1MS m/z 504 (5, M +), 372 (10); 240 (100); Anal.C 32H 24O 6(C, H).
Embodiment 15
1, and 5-disulfide group anthraquinone (1,5-bis-thioanthraquinones)
Weigh 1.0g (3.6mmol) 1,5-dichloride base anthraquinone (1.5-dichloroanthraquinone) adds 100ml tetrahydrofuran (THF) (THF), and be dissolved with 28.8mmol mercaptan (thiols, RSH) 1.56g (28.8mmol) sodium methoxide (sodium methoxide), under nitrogen, slowly splash into the 30ml anhydrous methanol, place the round bottom two-neck bottle.Reflux and after 1 hour reaction solution is poured in the 250ml water, get organic layer with dichloromethane extraction, with water with the impurity in flush away organic layer and the dichloromethane layer amalgamation layer, through anhydrous sodium sulphate absorption moisture and filtration wherein, gained solution is removed solvent with concentrating under reduced pressure, carries out purifying with the tubing string chromatography; Recrystallize.
Embodiment 16
1, two (ethyl the sulfenyl)-anthraquinones of 5-(1,5-Bisethylthio-anthraquinone, 2a):
66% productive rate; Mp 235-236 ℃ (THF); 1H-NMR (CDCl 3) δ: 1.45 (6H, t, J=7.4Hz), 3.10 (4H, q, J=7.4Hz), 7.60 (2H, d, J=8.0Hz), 7.66 (2H, t, J=7.8Hz), 8.11 (2H, t, J=7.6,0.9Hz), 13C-NMR (CDCl 3) δ: 12.77,25.96,123.47,127.89,129.26,133.14,136.09,145.03,183.33.IR (KBr) cm -11651,1202.UV λ Max(CHCl 3) nm (log): 503 (2.41) .MS m/z, 328 (M +), 299,267,239,139.Anal.Calcd.for C 18H 16O 2S 2: C, 65.82; H, 4.91.Found:C, 65.65; H, 4.88.
Embodiment 17
1, two (hydroxyethyl the sulfenyl)-anthraquinones of 5-(1,5-Bishydroxyethylthio-anthraquinone, 2b):
45% productive rate; Mp 261-262 ℃ (DMSO). 1H-NMR (CDCl 3) δ: 3.12 (4H, t, J=6.5Hz), 3.70 (4H, q, J=6.2Hz), 5.04 (2H, t, J=8.0Hz), 7.78 (2H, d, J=7.6Hz), 7.82-7.80 (2H, m), 7.94 (2H, dd, J=6.8,1.5Hz), 13C-NMR (CDCl 3) δ: 34.04,59.06,122.84,127.42,129.88,133.57,135.55,144.07,182.35.IR (KBr) cm -1: 1638,1204.UV λ Max(CHCl 3) nm (log): 513 (2.48) .MS m/z, 360 (M +), 324.Anal.Calcd.forC 18H 16O 4S 2: C, 59.98; H, 4.47.Found:C, 59.81; H, 4.38.
Embodiment 18
1, two (propyl group the sulfenyl)-anthraquinones of 5-(1,5-Bispropylthio-anthraquinone, 2c):
69% productive rate; Mp232-233 ℃ (THF). 1H-NMR (CDCl 3) δ: 1.13 (6H, t, J=7.4Hz), 1.83 (4H, m), 2.96 (4H, t, J=7.4Hz), 7.60 (2H, d, J=7.9Hz), 7.65 (2H, t, J=7.8Hz), 8.11 (2H, d, J=6.9Hz), 13C-NMR (CDCl 3) δ: 13.96,21.33,34.04,123.46,127.99,129.32,133.12,136.14,145.20,183.35.IR (KBr) cm -1: 1649,1199.UV λ Max(CHCl 3) nm (log): 485 (2.25) .MS m/z:356 (M +), 313,271,239,139.Anal.Calcd.forC 20H 20O 2S 2: C, 67.38; H, 5.65.Found:C, 67.55; H, 5.78.
Embodiment 19
1, two (hydroxypropyl the sulfenyl)-anthraquinones of 5-(1,5-Bisdihydroxypropyithio-anthraquinone, 2d):
45% productive rate; Mp 238-239 ℃ (DMSO). 1H-NMR (CDCl 3) δ: 2.93 (2H, t, J=10.1Hz), 3.20 (2H, dd, J=12.7,4.2Hz), 3.41-3.50 (4H, m), 3.73 (2H, m), 4.79 (2H, t), 5.12 (2H, d, J=5.3Hz), 7.79 (2H, t, J=7.7Hz), 7.82 (2H, d, J=7.4Hz), 7.94 (2H, t, J=7.3,0.8Hz) 13C-NMR (CDCl 3) δ: 35.53,65.05,69.91,122.75,127.39,130.02,133.56,135.55,144.71,182.41.IR (KBr) cm -1: 1647,1202.UV λ Max(CHCl 3) nm (log): 507 (2.48) .MS m/z:420 (M +), 348.Anal.Calcd.for C 20H 20O 6S 2: C, 57.12; H, 4.79.Found:C, 57.35; H, 4.98.
Embodiment 20
1, and two (hydroxyl hexyl the sulfenyl)-anthraquinones of 5-(1,5-Bishydroxyhexylthio-anthraquinone, 2e): 79% productive rate; Mp195-196 ℃ (DMSO). 1H-NMR (CDCl 3) δ: 1.37 (4H, q, J=6.9Hz), 1.46 (4H, q, J=6.9Hz), 1.49 (4H, q, J=7.5Hz), 1.70 (4H, q, J=7.3Hz), 3.00 (4H, t, J=7.2Hz), 3.41 (4H, q, J=5.9Hz), 4.10 (2H, t, J=5.1Hz), 7.77-7.80 (4H, m), 7.95 (2H, d, J=6.5Hz) 13C-NMR (CDCl 3) δ: 24.79,27.31,28.10,30.77,32.04,60.41,122.41,127.18,129.64,133.13,135.34,144.10,181.98.IR (KBr) cm -1: 1643,1259.UV λ Max(DMSO) nm (log): 564 (0.32) .MS m/z, 472 (M +), 474.Anal.Calcd.forC 26H 32O 4S 2: C, 66.06; H, 6.82.Found:C, 66.35; H, 6.98.
Embodiment 21
1, two (neighbour-amido phenolic group the sulfenyl)-anthraquinones of 5-(1,5-Bis (o-aminophenylthio)-anthraquinone, 2f):
55% productive rate; Mp 283-284 ℃ (DMSO). 1H-NMR (CDCl 3) δ: 5.37 (4H, s), 6.66 (2H, t, J=7.5Hz), 6.85 (2H, d, J=8.1Hz), 7.01 (2H, d, J=8.2Hz), 7.25 (2H, t, J=7.6,0.9Hz), 7.34 (2H, d, J=7.5Hz), 7.66 (2H, t, J=7.9Hz), 8.00 (2H, d, J=7.4Hz). 13C-NMR (CDCl 3) δ: 111.35,115.06,117.03,123.67,127.77,130.43,131.77,133.41,135.51,137.08,143.20,150.66,182.65.IR (KBr) cm -1: 1651,1256.UV λ Max(DMSO) nm (log): 508 (2.36) .MS m/z, 454 (M +), 361.Anal.Calcd.for C 26H 18N 2O 2S 2: C, 68.69; H, 3.99.Found:C, 68.55; H, 3.78.
Embodiment 22
1,5-pair (-amido phenolic group sulfenyl)-anthraquinone (1,5-Bis (m-aminophenylthio)-anthraquinone, 2g):
65% productive rate; Mp 292-293 ℃ (DMSO). 1H-NMR (CDCl 3) δ: 5.40 (4H, s), 6.71-6.73 (4H, m), 6.80 (2H, s), 7.16 (2H, d, J=8.3Hz), 7.19 (2H, t, J=7.8Hz), 7.67 (2H, t, J=7.9Hz), 7.97 (2H, d, J=7.5Hz). 13C-NMR (CDCl 3) δ: 115.41,120.04,122.24,123.57,126.59,130.74,130.94,131.01,133.49,135.10,145.53,150.44,182.42.IR (KBr) cm -1: 1653,1202.UV λ Max(DMSO) nm (log): 535 (2.48) .MS m/z, 454 (M +), 125.Anal.Calcd.for C 26H 18N 2O 2S 2: C, 68.69; H, 3.99.Found:C, 68.49; H, 3.69.
Embodiment 23
1, two (right-amido phenolic group the sulfenyl)-anthraquinones of 5-(1,5-Bis (p-aminophenylthio)-anthraquinone, 2h):
66% productive rate; Mp364-365 ℃ (DMSO). 1H-NMR (CDCl 3) δ: 5.64 (4H, s), 6.70 (4H, t, J=8.3Hz), 7.07 (2H, d, J=8.3Hz), 7.20 (4H, d, J=8.3Hz), 7.63 (2H, t, J=7.9Hz), 7.94 (2H, d, J=7.5Hz). 13C-NMR (CDCl 3) δ: 114.01,115.19,123.28,126.46,130.57,133.29,135.19,137.02,147.69,150.64,182.41.IR (KBr) cm -1: 1649,1283.UV λ Max(DMSO) nm (log): 557 (2.48) .MS m/z, 454 (M +), 124.Anal.Calcd.forC 26H 18N 2O 2S 2: C, 68.69; H, 3.99.Found:C, 68.49; H, 3.68.
Embodiment 24
1, two (benzyl the sulfenyl)-anthraquinones of 5-(1,5-Bisbenzylthio-anthraquinone, 2i):
78% productive rate; Mp 281-282 ℃ (THF). 1H-NMR (CDCl 3) δ: 4.23 (4H, s), 7.27 (2H, t, J=7.3Hz), 7.33 (4H, d, J=7.4Hz), 7.45 (4H, d, J=7.4Hz), 7.62 (2H, d, J=8.0Hz), 7.66 (2H, t, J=7.4Hz), 8.10 (2H, d, J=7.1Hz). 13C-NMR (CDCl 3) δ: 37.35,123.76,127.58,127.91,128.78,129.10,129.59,133.32,135.41,135.86,144.92,183.31.IR (KBr) cm -1: 1653,1261.UV λ Max(CHCl 3) nm (log): 476 (1.50) .MS m/z452 (M +), 361,270,91.Anal.Calcd.for C 28H 20O 2S 2: C, 74.30; H, 4.55.Found:C, 74.55; H, 4.78.
Embodiment 25
1, two (phenylethyl the sulfenyl)-anthraquinones of 5-(1,5-Bisphenylethylthio-anthraquinone, 2k):
69% productive rate; Mp209-210 ℃ (THF). 1H-NMR (CDCl 3) δ: 3.08 (4H, t, J=8.0Hz), 3.25 (4H, t, J=8.1Hz), 7.28 (2H, t, J=7.0Hz), 7.30 (2H, t, J=8.3Hz), 7.32 (2H, d, J=7.4Hz), 7.62 (2H, d, J=7.4Hz), 7.66 (2H, t, J=7.7Hz), 8.12 (2H, d, J=6.2Hz). 13C-NMR (CDCl 3) δ: 33.64,34.28,123.65,126.68,128.02,128.43,128.69,129.31,133.22,136.07,140.04,144.64,183.29.IR (KBr) cm -1: 1653,1204.UV λ Max(CHCl 3) nm (log): 512 (0.60) .MS m/z, 480 (M +), 285.Anal.Calcd.for C 30H 24O 2S 2: C, 74.96; H, 5.03.Found:C, 74.75; H, 4.91.
The cytotoxicity of table one chemical combination 1a-1n of the present invention and inhibition lipid peroxidation activity
Figure A0214470000221
Compound Substituting group (R) The concentration IC that suppresses cell strain 20(μM) Lipid peroxidation activity (10mM)
Hepatoma cell strain (Hep G2) Neuroglial cytoma strain (C6 cells)
????1a CH 2CH 3 ??4.1±0.5 ????21.1±1.6 ????-100
????1b CH 2CH 2CH 3 ??0.02±0.01 ????38.5±2.8 ????54±2.2
????1c CH 2CH 2CH 2CH 2CH 3 ??36.2±2.5 ????39.1±4.1 ????-55±1.5
????1d C(CH 3) 3 ??13.7±1.8 ????12.0±1.5 ????-23±1.1
????1e C 6H 5 ??47.7±5.5 ????38.7±3.6 ????-50±1.9
????1f 2-ClC 6H 4 ??0.04±0.01 ????40.7±4.7 ????5±0.5
????1g 3-ClC 6H 4 ??15.1±1.9 ????25.1±2.8 ????1±0.1
????1h 4-ClC 6H 4 ??48.1±4.5 ????38.6±3.5 ????2±0.2
????1i 2，4-ClC 6H 3 ????＞50 ????38.4±4.4 ????-1±0.1
????1j 2-CH 3C 6H 4 ??21.6±2.2 ????25.1±2.8 ????23±1.1
????1k 3-CH 3C 6H 4 ??18.1±1.5 ????30.1±3.3 ????-32±1.5
????1l 4-CH 3C 6H 4 ??9.3±0.9 ????37.6±4.1 ????33±1.2
????1m CH 2C 6H 5 ??9.0±1.5 ????39.1±6.2 ????-1±0.2
????1n CH 2CH 2C 6H 5 ??0.4±0.1 ????40.1±5.5 ????＞100
The appropriate father-in-law of wheat (mitoxantrone) ??2.0±0.5 ????0.07±0.01 ????＞100
Vitamin C (ascorbic acid) ????＞100
Vitamin E (+)-α-tocopherol ????＞100
Bank draws atmosphere (anthrarufin) ????-36±1.1
The cytotoxicity of table two The compounds of this invention 2a-2k and inhibition lipid peroxidation activity
Compound Substituting group (R) The concentration IC that suppresses cell strain 20(μM) Lipid peroxidation activity (10mM)
Hepatoma cell strain (Hep G2) Neuroglial cytoma strain (C6 cells)
????2a CH 2CH 3 ??12.2±1.1 ????0.02±0.01 ????83±2.2
????2b CH 2CH 2OH ??36.4±1.5 ????21.5±0.8 ????16±2.2
????2c CH 2CH 2CH 3 ??75.1±2.5 ????29.9±2.1 ????15±1.5
????2d CH 2CH(OH)CH 2OH 3 ??34.3±1.8 ????38.5±1.5 ????83±1.1
????2e (CH 2) 6OH ??49.3±2.1 ????31.7±1.6 ????54±1.9
????2f 2-NH 2C 6H 4 ??34.0±1.7 ????15.1±1.7 ????5±0.5
????2g 3-NH 2C 6H 4 ??21.5±1.2 ????26.3±2.8 ????6±0.9
????2h 4-NH 2C 6H 4 ??17.4±1.5 ????0.05±0.01 ????20±1.4
????2i CH 2C 6H 5 ??41.5±2.5 ????38.2±4.4 ????＞100
????2j CH 2C 6H 4(OCH 3)(p) ??28.6±1.2 ????25.1±2.8 ????67±2.9
????2k CH 2CH 2C 6H 5 ??36.9±1.5 ????32.9±3.3 ????69±1.5
The appropriate father-in-law of wheat (mitoxantrone) ??2.0±0.5 ????0.07±0.01 ????54±1.5
Vitamin C (ascorbic acid) ????＞100
Vitamin E (+)-α-tocopherol ????＞100
Bank draws atmosphere (anthrarufin) ????-36±1.9
The inhibition lipid peroxidation activity of table three The compounds of this invention 1n and 2i
Compound Inhibition concentration (%)
???10mM ???1mM ??0.1mM ??0.01mM
????1n ??＞100 ???＞100 ??95±2.0 ??50±0.8
????2i ??＞100 ????95 ??60±2.0 ??24±0.8
Vitamin C (ascorbic acid) ????100 ??75±1.5 ??32±1.2 ??10±0.6
Vitamin E (+)-α-tocopherol ????100 ??55±1.7 ????0 ????0
The appropriate father-in-law of wheat (mitoxantrone) ????100 ??54±2.1 ??22±3.5 ??5±0.3

Claims (10)

  1. It is 1, a kind of suc as formula the compound shown in the I,
    Figure A0214470000021
    Wherein, the R base is the alkoxyl group of 1 to 10 carbon atom, or selects alkyl for use, alkyl amine group, or amido alkoxyl group, and the amido alkyl, or the phenyl of alkoxyl group replacement is arranged, or the benzyl of alkoxyl group replacement is arranged; Or the phenyl of amido replacement is arranged, or the benzyl of amido replacement; Above-mentioned alkyl or alkoxyl group all can be straight chain, perhaps side chain; And the replacement of above halogens such as fluorine, chlorine, bromine, iodine can be arranged all on this alkyl, alkoxyl group, phenyl, the benzyl.
  2. It is 2, a kind of suc as formula the compound shown in the II,
    Wherein, the R base is the alkoxyl group of 1 to 10 carbon atom, or selects alkyl for use, alkyl amine group, or amido alkoxyl group, and amido gastral cavity base, or the phenyl of alkoxyl group replacement is arranged, or the benzyl of alkoxyl group replacement is arranged; Or the phenyl of amido replacement is arranged, or the benzyl of amido replacement; Above-mentioned alkyl or alkoxyl group all can be straight chain, perhaps side chain; And the replacement of above halogens such as fluorine, chlorine, bromine, iodine can be arranged all on this alkyl, alkoxyl group, phenyl, the benzyl.
  3. 3, a kind of preparation is suc as formula I, the method of compound shown in the formula II, weigh bank and draw atmosphere or 1,5-dichloride base anthraquinone (1,5-dichloroanthraquinone) place the round bottom two-neck bottle, add anhydrous methylene chloride or tetrahydrofuran (THF) and add pyridine or sodium hydride subsequently, after evenly stirring 30 minutes under 0 ℃, slowly splash into an amount of halogenation vinegar compound or mercaptan, sodium methoxide, after continuing to be stirred to room temperature or heating, reaction solution poured into get organic layer in the water, with dichloromethane extraction, remove impurity in organic layer and the dichloromethane layer amalgamation layer with washing, through anhydrous sodium sulphate absorption moisture and filtration wherein, gained solution is removed solvent with concentrating under reduced pressure, carries out purifying with the tubing string chromatography; Add ethanol, tetrahydrofuran (THF) or disulfoxide recrystallize, can obtain formula I compound 1, and the two anilide oxygen anthraquinones of 5-(1,5-bisacyloxyanthraquinone), and formula II compound 1,5-disulfide group anthraquinone (1,5-bis-thio-anthraquinones).
  4. 4, in accordance with the method for claim 3, its mercaptan compound or halogenation vinegar raw materials of compound, can select that the R base is the alkoxyl group of 1 to 10 carbon atom on its structure for use, alkyl, alkyl amine group, or amido alkyl, or amido alkoxyl group, or the phenyl of alkoxyl group replacement is arranged, or the benzyl of alkoxyl group replacement; Or the phenyl of amido replacement is arranged, or the benzyl of amido replacement; Above-mentioned alkyl or alkoxyl group all can be straight chain, perhaps side chain; And the replacement of above halogens such as fluorine, chlorine, bromine, iodine can be arranged all on this alkyl, alkoxyl group, phenyl, the benzyl.
  5. 5, the pharmaceutical compositions of a kind of antianaphylaxis, inflammation, it is to contain to possess compound shown in the dosage formula I, and pharmaceutically acceptable excipient.
  6. 6, the pharmaceutical compositions of a kind of antianaphylaxis, inflammation, it is to contain to possess compound shown in the dosage formula II, and pharmaceutically acceptable excipient.
  7. 7, a kind of antitumor pharmaceutical compositions, it is to contain to possess compound shown in the dosage formula I, and pharmaceutically acceptable excipient.
  8. 8, a kind of antitumor pharmaceutical compositions, it is to contain to possess compound shown in the dosage formula II, and pharmaceutically acceptable excipient.
  9. 9, the super oxygen dismutase of a kind of influence suppresses the pharmaceutical compositions of superoxide ion generation, and it is to contain to possess compound shown in the dosage formula I, and pharmaceutically acceptable excipient.
  10. 10, the super oxygen dismutase of a kind of influence suppresses the pharmaceutical compositions of superoxide ion generation, and it is to contain to possess compound shown in the dosage formula II, and pharmaceutically acceptable excipient.
CNA021447004A 2002-12-04 2002-12-04 1,5-double substituted anthraquinone derivative, synthetic method and uses thereof Pending CN1504453A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102604097A (en) * 2012-03-14 2012-07-25 吉林大学 Anthraquinone-contained polyphenylene sulfone copolymer and synthetic method thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102604097A (en) * 2012-03-14 2012-07-25 吉林大学 Anthraquinone-contained polyphenylene sulfone copolymer and synthetic method thereof
CN102604097B (en) * 2012-03-14 2013-10-23 吉林大学 Anthraquinone-contained polyphenylene sulfone copolymer and synthetic method thereof

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